Preparation of aromatic diazonium fluoborate



Patented Aug. 5, 1952 FLUOBORATE James D. Head and Frederick J.

Lewes, Midland,

Mich, assignoi's to The Dow Chemical Company, Midland, Mich, acorporation oi Delaware No Drawing.

This invention relates to the preparation of fiuoro-sub'stltuted aromatic compounds, and,

more particularly, to an improvement in a method for producing such materials.

Aromatic fiuoro compounds have been produced Application October 3, 1949, Serial No. 119,393 3 Claims. (01. sea-141) HP (1. e., more than four mols of HF per mol of by the Balz=schiemann reaction '(Berichte, vol. '60, I

p. 1186 et seq. (1927)), sometimes called the Schie'mann reaction. According to this reaction a primary aromatic amine is converted to the corresponding fluoride by three separate steps: (1) diazotizing the amine hydrochloride by means of sodium nitrite and hydrochloric acid to produce a diazonium chloride; (2) converting the diazonium chloride to the diazonium fluoborate by the action of fluoborio acid; and (3) thermally decomposing the diazonium v responding fluoride. Dazotiz'ationi's carried out in a solvent that comprises hydrochloric acid.

The reactions whichare believed to proceed in' the course of the overall process are illustrated by Equations 1, 2 and 3, below, 1 (1) RNH3Cl+NaNQz=|=HCl= RN2Cl+2H20+NaCl (2) RN2C1+HBF4+ RN2BF4+HCL (3) RN2BFr RF+N2+BF3 in which R is an aromatic radical. Thisgeneral method is applicable to the preparation of fluorosubs'tituted aromatic compounds useful as intermediates for the production of oxygen-carrying chelates. g 7

Of like utility is a known improvement on the BaIZ-Schiem'ann reaction in which the diazotization is carried out in a solvent comprising fluoboric acid (see Organic syntheses, vol. XIX, 'p. 40) When the diaz'otization is conducted in this way, the desired diazonium fiuoborate is produced directly from the amine reactant in Ta singlestep. The reaction which is believed to occuris illustrated by Equation 4, below,

4) RNl-Iz+NaNOz+2H F4? I 7 y in which R is an aromatic radical. I

The present invention is based upon the discovery of a further improved way of producing a diazoni-um fiuoborate which results in a substantially better yield of the aromaticfluoride after decomposition than is possible with either, of the prior processes. Thisfurther improvement is applicable whether the diazotization solvent is an aqueous solution comprising hydrochloric acid (original Balz-Schiemann reaction) or an aqueous solution comprising fluoboric acid (improvedmethod shown in Organic Syntheses) In accordance with the invention, an excess of boric acid) is provided in the fiuoboric acid solution used to form the diazonium fluoborate (i. e., the fluoboric acid solution used to convert the diazonium chloride to diazonium fiuoborate when hydrochloric acid is thediazotization solvent, or the fluoboric acid solution used as the diazotization solvent). I r I A preferred embodiment of the invention involves using an aqueous, solution that comprises fluoboric acid and excess HF as solvent for conducting the diazotization reaction. This embodi ment is preferred because itaccomplishes a substantially greater conversion'of the amine to the fluoride (based upon the-fluoboric acid consumed) fluoborate to the cor- Even a slight excess of HF in the fluoboric acid used-to form the diazonium fiuoborate results in a substantially-improved yield of the aromatic fluoride. In order to realize the maximum benefit from theuse of excess HF it is usually preferred to use a sufiicient excess of HF that the molar ratio of HF to. boric acid (used to prepare the fluoboric acid) be at least-4.121, and most preferred to use a s'ufiicientexce'ss that it be at least 4.2:1; there is no reason for the ratio to be more than 5:1. j

Although the invention is not limited to the following theoretical explanation, it is'believed that the substantially improved yields achieved from the method of the invention indicate that an equilibrium prevails in a fluobo'ric acid solution, and that the presence of anexcess of HF drives this equilibrium in a direction that favors the formation of the desired product. A possible equilibrium, the existence of which could interfere with-the formation of the desired product, is illustrated by Equation'5, below,

It is thought that'such an equilibrium prevails between fluoboric acid and water, and that I-IBFaOI-l forms diazonium SaltsfiR-NzBfiOH) which do not undergo thermal decomposition to form the corresponding fluorides.

In general, any primary aromatic amine can be converted to the corresponding fluoride according to the improved methods of the invention. Secondary and tertiary amines are not applicable because they do not undergo diazo-tization. Although certain radicals attached as substituents to the aromatic nucleus tend to interfere with the diazotiaation, a better yield results from the improved method even though the aromatic amines include interfering substituents. Eiramples of such interfering substituents include stituents. Halo, alkyl and alkoxy substituents in no way interfere with the diazotization and formation of the diazonium fluoborate; furthermore, primary amines including such radicals yield fluoro-substituted aromatic compounds having particular utility for the production of oxygen-carrying chelates (see J. Am. Chem. Soc., vol. 68, page 2254 et seq.). Accordingly, the use of a primary aromatic amine whose molecular structure includes a halo, an alkyl or an alkoxy substituent is a preferred embodiment of the invention. The most preferred embodiment involves the use of a primary aromatic amine whose molecular structure includes all three of these substituents (i. e., halo, alkyl and alkoxy). The halo substituents can be fluoro, chloro, bromo or iodo. The alkyl substituent, or the alkyl part of the alkoxy substituent, can be primary, secondary or tertiary; the number of carbon atoms is limited only by practical considerations, which usually make it desirable that the alkyl or alkoxy radicals have not more than about sixteen carbon atoms, that the aromatic nucleus be a phenyl or naphthyl ring, and that there be not more than five substituents, other than amino, attached to the aromatic nucleus.

In effecting diazotization of a primary amine according to the invention, it has been found advantageous to use an approximately equimolecular amount of a nitrite, any excess being of the nitrite. About a five per cent excess of the nitrite is ordinarily most desirable. The diazotization is preferably conducted at a tem perature between about C. and about C., although higher temperatures. e. g., as high as about 25 C., canbe used; however, a lower yield of the diazonium fluoborate ordinarily results when the reaction is conducted at a temperature higher than about 0 C. Cooling is conveniently effected by means of a refrigerant or with Dry Ice, which also provides an inert gas (CO2) atmosphere which is desirable during diazotization in an open vessel. The nitrites that are used are ordinarily alkali metal nitrites because of their solubility in the aqueous diazotization solutions.

Diazotization is conveniently effected by dissolving the primary aromatic amine in the diazotization solvent (i. e., either aqueous hydrochloric acid or aqueous fluoboric acid) and adding the nitrite to the resulting solution. Stirring of the medium during the addition of the nitrite substantially increases the yield. Diazotization proceeds readily, and it is ordinarily desirable that the nitrite be added comparatively rapidly. However, if the rate of nitrite addition is too high, N02 is released from the diazotization mixture by undesirable side reaction. Accordingly, the nitrite is ordinarily added at a rate just lower than that at which N02 evolution occurs (e. g., in about 30 minutes if the diazotization temperature is 10 C., or in about 60 minutes if the diazotization temperature is approximately 0 C.). While the nitrite is conveniently added to the diazotization mixture as an aqueous solution, the introduction of unnecessary water into the reaction ves sel is usually avoided by employing a nitrite solution that is approximately saturated. When the nitrite addition is complete, the diazotization mixture is preferably warmed to a temperature between about 20 C. and about 30 C. in order to assure completion of the reaction. I

It is usuallydesirable that the molar ratio of fiuoboric acid to aromatic amine be from about 1:1 to about 4:1. It is most desirable that the molar ratio 01 fiuoboric acid to aromatic amine be about 2:1 to 3:1. The preferred ratios of fluoboric acid to aromatic amine are a compromise, because a low ratio of fluoboric acid to aromatic amine results in incomplete precipitation of the diazonium fluoborate, and too high a ratio makes recovery of the excess fluoboric acid unreasonably diflicult.

When the diazotization is carried out in a solvent that comprises fluoboric acid, formation of the diazonium fluoborate takes place at the same time that the diazotization reaction occurs, and the temperature at which the diazonium iiuoborate isi'ormed is the temperature at which the diazotization is carried out. When the diazotization is carried out in an aqueous hydrochloric acid solution the diazonium fluoborate is formed by subsequent additions of fluoboric acid and excessHF. Since, as is indicated above, the diazotization product has usually been warmed to a temperature between about 20 C. and about 30 C., thefluoboric acid and excess HF are conveniently added to the warm solution with further cooling only to keep the temperature thereof from exceeding 30 C.

After the diazonium fluoborate has been formed, it is separated from the reaction solution, e. g., by filtration or by centrifuging. Because the diazonium fluoborate is substantially solublein the warm reaction solution, it is usually desirable that the entire mixture be cooled to reduce the solubility of the fluoborate before the separation is accomplished. Ordinarily cooling to temperatures of from about 20" C. to about -30 C. is satisfactory.

Following separation the diazonium fluoborate may advantageously'be washed with an organic material such as ethylene dichloride. The washed materialis then dried, in air alone or in a vacuum. It is extremely important that all moisture be separated from the diazonium fluoborate before thermal decomposition is effected; even a comparatively small amount of moisture interferes substantially with decomposition and greatly reduces the yield of the final fluoride. The thermal decomposition is efiected by the usual methods (e. g., those disclosed by Balz and Schiemann).

The following examples illustrate the new process, but are not to be construed as limiting the scope of the invention.

EXALELEI A primary aromatic amine was converted to the corresponding fluoride according to the following procedure:

Aniline (93 grams) and an aqueous solution of fluoboric acid produced from hydrofluoric acid (442 grams of an aqueous solution containing 60 per cent of HF), boric acid grams) and water (200 grams) were added to a copper beaker equipped with a motor driven stirrer fitted with copper paddles. The acid solution comprised fluoboric acid and excess HF in such proportion that the ratio of F to B in the solution was 4.421. The resulting solution was cooled to a temperature between 5 C. and 10 C. by adding pulverized Dry Ice to the beaker. While this temperature was maintained by additions of pulverized Dry Ice-aqueous sodium nitrite was added over a period of 4'5 minutes. with vigorous stirrin (a total of 150 milliliters of a solution containing '70 grams of sodium nitrite). The rate of sodium nitrite addition was the maximum that could be used without liberation of N02. The material was then allowed to warm to a temperature of 20 C. to assure completion of the diazotization, after which itwas cooled to about 25 C. to complete precipitation of. the. diazoni'um' ffluo borate. The precipitatejwa's collected by passing the cooled reaction products through a basket centrifuge fitted with a Saran fabric sack. The collected precipitate was washed with ethylene dichloride (250 cc.) .anddried about lfihours at room temperature at a totalpressure'or irom about three to about eight inches or mercury. The precipitate collected was about 192 grams. A sample of the dried precipitate (60 grams) was decomposed to vfiuorobenzene (19.8 grams). Theoverall conversion zenewas thus about 66-per cent. The decomposition was accomplished by-placing the washed and dried precipitate in a flask fitted with an outlet train passing in sequence-through a water.- ice slurry, and a sodium hydroxide solution,and

or aniline to: fiuorobenousacid and 389 cc. or water) piazotization was accomplished by sodium r'iitrite additions ftojthe cooled solution as described in Example 1. The diazotization products were allowed to warm to 20 C. to insure compltiorrof the diazotization reaction, and fluoboric acid (produced irom boric acid, 136 grams and hydrofluoric acid, 325 grams of a 60 per cent aqueoussolution) was added thereto. The acid solution comprised fluoboric acid and excess HF in such proportion that the ratio of F to B was 4.4:1. The solution was then cooled to about -25 C. to complete precipitation of the fluoborate, and the solids were separated and fluoroben'zene (54 grams). recovered'as described above. This amounts, to afi'lidpercent conversion of the aniline hydrochloride charged to fluorobenzene. w W

Theprocedure of Examplelwas used toproduce three other aromatic fluorides (runs 2, 4 and 5 in Table I) and the procedure of Exampie 2 was used to produce-twoarornatic fluorides (runs 1 and 3 in Table I). The-stepsin these preparations andthe starting materialsand products are summarized in: Table Lbelow.

7 Table I Boric acid (gms) Hydrofluoric (gms.) Water (00.) Hydrochloric (cc.) acid 1 Ratio of F to B Diazotization temperature in C Temperature (C.) to which diazotized amine was warmed after diazotization 1 lluoboric acid precipitation:

Boric acid (g-ms.) Hydrofluoric (gms) ac1d Ratio of F to B Temperature G. of fluoborate before wheeling.

Product Grams of Product Per cent conversion product 1 Hydrofluoric acid: 60 per cent aqueous. 1 Hydrochloric acid: 37 per cent aqueous.

thence to a vacuum line. The entire surface of the flask was heated to insure escape of all liquid products, the heating being continued to dull redness. The condensates in the ice and sodium hydroxide traps were combined and the organic material recovered by steam distillation. The organic layer in the distillate was separated and. dried over calcium chloride (about 10 grams). Pure fiuorobenzene was isolated by a final distillation. 1

EXAMPLE 2 v A procedure similar to that described inExample 1 was employed to convert aniline hydrochloride to fluorobenzene; the Principal difference was that diazotization was carried out in .a hydrochloric acid solution..- Aniline hydrochloride (129.5 grams) was mixed with a hydrochloric acid solution (320 cc. of 37 per centaque- 20 2(] -20 l-fluorol-fluorop-fluoro p-fluoro a-fluoro i-bromo 4-bromoamsole auisole naphthalene benzene benzene Table I shows the suitability or thefr'nethod of the invention to the productiori of various aromatic fluorides, whether. .diazotization is carried out in a solvent that comprises fluoboric acid and excess HF, or whether diazotization is carried out in a solvent that comprises hydrochloric acid and the fluoborate subsequently precipitated with a solution comprising fluoboric acid and excess HF. 1

EXAMPLE 4 I The procedure of Example 1 was also used in the production of aromatic fluorides in comparative studies where all variables were maintained approximately constant except the ratio of HF to HsBOa used in preparing the fluoboric acid. The steps in preparations usinghydrofluoric acid as the diazotizationsol ifilitji andithe sta un materials and products are summarized inTable Diarotization's'olvent: QI Q acid. (e s compound. Fromvi-chlorq-Z-fluoroanisole, by theusual method, 4-chloro-2v-fiuoro phenol 1 J 3 I v is produced; 4-chloro- 2-fluoro phenol} believed also to be a new compound, has a'boiling point of 103 C. to104 C. at 50 mm. of mercury; "Table IlI' demonstrates clearly the advantage of the method oi. the invention in that it shows the substantially improved yield which, results z$ s -le 1 from carrying out precipitation or the fluoborate Ratio orr'ib'isl'jIII 4.41 V 4.0;1 with a fluoborieacid solution comprising e'xcess Diazotization temperature O. l 5 to 'HF' I v v i J Temperature (C.) to which diszo- I v I r tired amine was warmed after dia- EXAMPLE 6 I lotization 10 Tz f ggfgg I fllllmm b' H 1 20 The advantage of using a solution comprising P aucamIIII" 'z-fluoro 2-fl uor o fluoboric acid as the diazotization solvent is illus- 'trated by Table IV, below in which the yields of G i 70 54 rr og z g i of amine toltlie fluorides (based upon the fluoboric acid used) for fluoride product t -l- 5 the preparations shown in Examples 1 and 2,

i V. v H and for the five runs shown in Table I are reig gg a ggs gg gg ggggi Dorted. a I

y 1.1011080 peroeu q Table EXAMPLE 5 1; T Diaw Per-cent Run tizatiou Ywld The procedure of Example 2 was used in the Solvent $382282?) production of aromatic fluorides in comparative studies where all variables were maintainedap- A 66 proximately constant except the ratio of HF to 33 26 HaBOa used in preparing the fluoboric acid. The E steps in preparations using hydrochloric acid as 35 D 28 the diazotization solvent, and the starting mas terials and products are summarized in Table III,

below, in which run 8 is not in accord with the invention since the ratio of F to B is 3.821.

A-Aqueous solution comprising fluoboric acid. B-Aqueous solution comprising hydrochloric acid.

Table III Run 8 9 V 10 in OCH; OCH; on, Am G iCl NHiCl NHJCI l U] l Diszotizstion solvent:

Hydrochloric acid (grns) 320 320 320 Water (00.) 380 330 380 Diazotization temperature in C. 5 to -10 5 to l0- 6 to -10 Temperature (C.) to which dia- 20 20 20 zotized amine is warmed alter ri fi 1 itat'on uo ric aci prec p l Boric acid (gms.). 136 136 136 Hydrofluoric (gms) acid 275 300 325 Ratio oiFto B 3.8:1 4.1:1 4,4;1 Temperature 01 fluoborate before 20 20 2Q Pr ei i ii t fil 4-chl0r02- 4-chloro-2 4-ch1om-2 i iluoro iluoro fluoro anisole am'sole 80 auisole 6 G am iP'oduct 8 Per cert ool iversion of amine to the v 21. 2 .50 3. 7

fluoride product. V

I Hydrochloric acid: 37 per cent aqueous. 1 Fluoboric acid: per cent aqueous.

The 4-chloro-2-fluoro anisole produced It is clear from Table IV that the preferred OCH: method or the invention (1. e., carrying out diazo- F tization ina solvent that comprises fluoboric acid and excess HF) requires substantially less fluoborlc acid p pound ofarnine converted to the corresponding fluoride.' In runs 1, 3, and Exam. ple 2 (where the solvent was hydrochloric acid),

(n :1.5163;-boiling pointat 102' c; to 193 c.

the average yield (based 'on fiuoborate) was 27 at 48 mm. of mercury) is believed to bea new per cent, whereas in runs 2, 4; 5, and Example 1 (where the solvent was fiuoboric acid), the average yield was 67 per cent.

We claim:

1. A method of producing an aromatic diazonium fluoborate that comprises treating the corresponding primary amine with (a) a nitrite, and (b) an aqueous solution that comprises fluoboric acid and hydrofluoric acid in such relative proportions that the ratio of F to B in the solution is at least 4.121 but not greater than 5:1.

2. A method of producing an aromatic diazonium fiuoborate that comprises treating the corresponding primary amine, dissolved in an aqueous solution that comprises fluoboric acid and hydrofluoric acid in such relative proportions that the ratio of F to B in the solution is at least 4.1:1 but not greater than 5:1, with a nitrite to produce the diazonium fluoborate.

3. A method as claimed in claim 2 in which the primary amine has the general formula RNH2 in which R. is a haloalkoxy alkaryl radical where- 10 in the alkoxy and alkyl groups have not more than 16 carbon atoms.

JAMES D. HEAD. FREDERICK J. LOWES.

REFERENCES CITED The following references are of record in the file of this patent:

FOREIGN PATENTS Number Country Date 600,706 Germany July 12, 1934 OTHER REFERENCES Fiat Final Report 998, March 31, 1947, pages 1 to 3.

Mellor, Inorganic and Theoretical Chemistry, vol. 5, page 124.

Balz et al., Ber. Deutsch. Chem. GeselL, vol. 603, pages 115 to 118 (1927).

Starkey et al., Organic Syntheses, vol. 19, pages 40-42 (1939). 

2. A METHOD OF PRODUCING AN AROMATIC DIAZONIUM FLUOBORATE THAT COMPRISES TREATING THE CORRESPONDING PRIMARY AMINE, DISSOLVED IN AN AQUEOUS SOLUTION THAT COMPRISES FLUOBORIC ACID AND HYDROFLUORIC ACID IN SUCH RELATIVE PROPORTIONS THAT THE RATIO OF F TO B IN THE SOLUTION IS AT LEAST 4.1:1 BUT NOT GREATER THAN 5:1, WITH A NITRITE TO PRODUCE THE DIAZONIUM FLUOBORATE. 